title: Germline variants and advanced colorectal adenomas: adenoma prevention with celecoxib trial genome-wide association study.
abstract: OBJECTIVE
  Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas.
  
  
  METHODS
  Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10(-7). Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58].
  
  
  RESULTS
  Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P < 10(-7) level with OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r(2) = 0.8-1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50-2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211).
  
  
  CONCLUSIONS
  Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance.
authors.affiliation: Authors' Affiliations: Department of Surgery, Division of Surgical Oncology, Center for Genomic Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts; Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California; Department of Epidemiology and Statistics, Memorial Sloan-Kettering Cancer Center, New York; RIKEN Center for Genomic Medicine, Tokyo, Japan; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Edinburgh; Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom; Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville; Genetic and Molecular Epidemiology Laboratories, and Familial Cancer laboratory, Queensland Institute of Medical Research, Brisbane; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; and Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Jen-Hwa
authors.initials: JH
authors.lastname: Chu
authors.forename: Ann G
authors.initials: AG
authors.lastname: Zauber
authors.forename: Michikai
authors.initials: M
authors.lastname: Kubo
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dunlop
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Oliver
authors.initials: O
authors.lastname: Sieber
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000517:prevention & control; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000517:prevention & control; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000517:prevention & control; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011720:Pyrazoles / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D016588:Anticarcinogenic Agents; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib